Phosphoinositide Metabolism In Rat Brain Research Articles

Chronic dexamethasone administration decreases noradrenaline-stimulated, but not serotonin-stimulated, phosphoinositide metabolism in the rat brain.

The present study was undertaken to investigate the effects of chronic administration of dexamethasone on the noradrenaline- and serotonin-stimulated (5-HT-stimulated) phosphoinositide metabolism in hippocampus and frontal cortex of the rat brain. For determination of phosphoinositide metabolism, slices from selected regions of the rat brain (hippocampus or frontal cortex) were loaded with myo- [3H] inositol and stimulated with the agonists (noradrenaline or 5-HT) in the presence of LiCl (7.5 mM). Administration of dexamethasone (1 mg/kg/day) every 2nd day for 14 days markedly reduced the noradrenaline-stimulated phosphoinositide metabolism in the rat hippocampus (IP1: 60% of the control value). In the rat frontal cortex, the noradrenaline-stimulated phosphoinositide metabolism was less depressed by the chronic administration of dexamethasone (IP1: 84% of the control value). However, the chronic administration of dexamethasone did not affect the 5-HT-stimulated phosphoinositide metabolism in the rat brain. The binding characteristics of alpha 1 -adrenoceptors and 5-HT2A receptors were unaffected by the chronic treatment with dexamethasone. These results indicate that chronic administration of dexamethasone induces regional and neurotransmitter-specific changes of phosphoinositide metabolism in rat brain. The results suggest that the reduction of noradrenaline-stimulated phosphoinositide metabolism is due to modification of the intracellular signal transduction system.

Postnatal development of muscarinic receptor-stimulated phosphoinositide metabolism in mouse cerebral cortex: sensitivity to ethanol

An enhanced coupling of cholinergic muscarinic receptors to phosphoinositide metabolism had been previously observed in brain from immature rat. This study reports that the postnatal development of muscarinic receptor-stimulated phosphoinositide metabolism is also enhanced in cerebral cortex slices from immature Swiss-Webster and Balb-c mice, as compared to adults. Response to the agonist carbachol was lower on postnatal day 3, peaked between days 5 and 12 and then declined to adult levels. Density of muscarinic binding sites, measured with the M 1 ligand [ 3H]telenzepine on postnatal day 7, was, on the other hand, only half of the adult value. Phosphoinositide hydrolysis stimulated by glutamate decreased with age, while that elicited by norepinephrine increased. These results are also similar to those previously reported in the rat. Ethanol has been found to inhibit muscarinic receptor-stimulated phosphoinositide metabolism in rat brain in an age-dependent manner. This was confirmed in mouse brain, where ethanol inhibited this response in cerebral cortex of immature but not adult animals. These results indicate that the enhanced muscarinic receptor-stimulated phosphoinositide metabolism, which coincides with the brain growth spurt, is similar in rats and mice. Mice may be a useful species in which to genetically manipulate muscarinic receptors to gain a better understanding of their potential role in brain development.

Aging-induced decrease in dopaminergic-stimulated phosphoinositide metabolism in rat brain

Accumulation of [ 3H]inositol phosphate and [ 3H]inositol labeling of phosphoinositides were evaluated in brain slices of 3-, 6-, 12-, and 24-month-old Fischer-344 rats. The dopamine agonist, SKF38393, stimulated significantly lower accumulations of inositol trisphosphate, inositol bisphosphate, and inositol monophosphate in the striatum, hippocampus, and frontal cortex of 24-month-old rats compared with the 6-month-old animals. No differences, however, were observed between the 3, 6, and 12-month-old groups. Furthermore there were marked decrements of 41% to 58% in the labeling of phosphoinositides in the different brain regions of the aged animals. Dose-response studies in forebrain slices of the 6-month-old and 24-month-old animals showed aging-related decrements of 53% ( p < 0.001) and 48% ( p < 0.001) in the maximal SKF38393-stimulated labeling of phosphoinositides and accumulation of inositol phosphates, respectively. These data suggest that aging of the rat brain is associated with alterations in the basal turnover of the inositol cycle and in the sensitivity of the transduction pathway to dopamine receptor stimulation.

Regional development of carbachol-, glutamate-, norepinephrine-, and serotonin-stimulated phosphoinositide metabolism in rat brain

Phosphoinositide metabolism stimulated by activation of cholinergic muscarinic, glutamatergic, α-adrenergic and serotoninergic receptors was measured in brain regions of the developing rats. Accumulation of [ 3H]inositol phosphates ([ 3H]InsPs) in [ 3H]inositol-prelabeled slices from cerebral cortex, hippocampus, brainstem and cerebellum was measured as an index of phosphoinositide metabolism. Large age-, neurotransmitter receptor-, and brain region-dependent differences were found. Carbachol-stimulated [ 3H]InsPs accumulation peaked on postnatal day 7 in cerebral cortex and hippocampus while in cerebellum and brainstem the effect of muscarinic stimulation was maximal at birth and then declined to adulthood. The effect of glutamate also showed a peak on day 7 in hippocampus and brainstem and a developmentally related decrease in cerebral cortex. In the cerebellum, on the other hand, the response to glutamate remained sustained through adulthood. Stimulation of phosphoinositide metabolism by norepinephrine increased with age in hippocampus and cerebral cortex, but decreased in the cerebellum, while the effect of serotonin did not change significantly with age except in cerebellum. These changes in receptor-stimulated phosphoinositide metabolism do not parallel, for the most part, the ontogeny of receptor recognition sites. Activation of the phosphoinositide metabolism pathway leads to an increase in intracellular calcium levels and to stimulation of protein kinase C, which are believed to play significant roles in cellular proliferation and differentiation. Thus, the differential ability of neurotransmitters to stimulate phosphoinositide hydrolysis might play a role in the development of brain regions.

Inhibitors of Na/K-ATPase stimulate phosphoinositide metabolism in rat brain

Inhibitors of Na/K-ATPase stimulate phosphoinositide metabolism in rat brain

σ Receptors negatively modulate agonist-stimulated phosphoinositide metabolism in rat brain

σ Receptors negatively modulate agonist-stimulated phosphoinositide metabolism in rat brain

Modulation of the activity of purified phosphatidylinositol 4-phosphate kinase by phosphorylated and dephosphorylated B-50 protein

To investigate the modulation of phosphatidylinositol 4-phosphate kinase activity by the degree of phosphorylation of the B-50 protein, the enzyme was purified from rat brain cytosol by ammonium sulphate precipitation and DEAE-cellulose column chromatography. Purified rat brain B-50 was phosphorylated with protein kinase C and dephosphorylated with alkaline phosphatase. Incubation of the semi-purified phosphatidylinositol 4-phosphate kinase with 1 μg of the B-50 preparation enriched in the dephospho-form, resulted in a small reduction of phosphatidylinositol 4-phosphate kinase activity (−16%), whereas incubation with the phospho B-50 preparation inhibited the enzyme activity by 40%. The effect of exogenous B-50 was studied in the presence of 10 μg albumin to minimize aspecific protein-protein interactions. The present data on the effect of exogenous B-50 protein on phosphatidylinositol 4-phosphate kinase activity, further support our hypothesis that the phosphorylation state of B-50 may be a regulatory factor in phosphoinositide metabolism in rat brain.

Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis.

A single subcutaneous dose of 10 mEq/kg LiCl gives rise to an increase in the cerebral cortex level of myo-inositol-1-P (I1P) that closely follows cortical lithium levels and, at maximum, is 40-fold above the control value. Kidney and testis show smaller increases in I1P level following LiCl administration. The I1P level is still sixfold greater than that of untreated rat cortex 72 h later. In cortex, parallel increases also occur in myo-inositol-4-P (I4P) and myo-inositol 1,2-cyclic-P (cI1,2P), whereas myo-inositol-5-P (I5P) remains unchanged. The cortical increases in I1P and I4P levels are partially reversed by administering 150 mg/kg of atropine 22 h after the LiCl, treatment that does not affect cI1,2P. When doses of LiCl from 2 to 17 mEq/kg are given, the cerebral cortex levels of I1P and myo-inositol, measured 24 h later, are found to reach a plateau at about 9 mEq/kg of LiCl, whereas cortical lithium levels continued to increase with greater LiCl doses. Levels of all three of the brain phosphoinositides are unchanged by the 10 mEq/kg LiCl dose, as is the uptake of 32Pi into these lipids. Chronic dietary administration of LiCl for 22 days showed that the effects of lithium on I1P and myo-inositol levels persist for that period. Over the course of the chronic administration of the lithium, levels of I1P, myo-inositol, and of lithium in cortex remained significantly correlated. We believe that these increases in inositol phosphates result from endogenous phosphoinositide metabolism in cerebral cortex and that lithium is capable of modulating that metabolism by reducing cellular myo-inositol levels. The size of the effect is a function of both lithium dose and the degree of stimulation of receptor-linked phosphoinositide metabolism. This property of lithium may explain part of its ability to moderate the symptoms of mania. Our chronic study suggests that prolonged administration of LiCl does not result in compensatory changes in myo-inositol-1-P synthase or myo-inositol-1-phosphatase.